Two formidable barriers to effective drug delivery and hence to disease treatment, are solubility and stability. To be absorbed in the human body, a compound has to be soluble in both water and fats (lipids). Solubility in water is, however, often associated with poor fat solubility and vice versa.
Over one third of drugs listed in the U.S. Pharmacopoeia and about 50% of new chemical entities (NCEs) are insoluble or poorly insoluble in water. Over 40% of drug molecules and drug compounds are insoluble in the human body. In spite of this, lipophilic drug substances having low water solubility are a growing drug class having increasing applicability in a variety of therapeutic areas and for a variety of pathologies. There are over 2500 large molecules in various stages of development today, and over 5500 small molecules in development (See Drug Delivery Companies Report 2001, p. 2, www.pharmaventures.com). Each of the existing companies focusing on these large and small molecules has its own restriction and limitations with regard to both large and small molecules on which they focus.
Solubility and stability issues are major formulation obstacles hindering the development of therapeutic agents. Aqueous solubility is a necessary but frequently elusive property for formulations of the complex organic structures found in pharmaceuticals. Traditional formulation systems for very insoluble drugs have involved a combination of organic solvents, surfactants and extreme pH conditions. These formulations are often irritating to the patient and may cause adverse reactions. At times, these methods are inadequate for solubilizing enough of a quantity of a drug for a parenteral formulation. In such cases, doctors may administer an “overdosage”, such as for example with poorly soluble vitamins. In most cases, this overdosage does not cause any harm since the unabsorbed quantities exit the body with urine. Overdosage does, however waste a large amount of the active compound.
The size of the drug molecules also plays a major role in their solubility and stability as well as bioavailability. Bioavailability refers to the degree to which a drug becomes available to the target tissue or any alternative in vivo target (i.e., receptors, tumors, etc.) after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. Poorly water soluble drugs tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation. It is known that the rate of dissolution of a particulate drug can increase with increasing surface area, that is, decreasing particle size
Recently, there has been an explosion of interest in nanotechnology, the manipulation on the nanoscale. Nanotechnology is not an entirely new field; colloidal sols and supported platinum catalysts are nanoparticles. Nevertheless, the recent interest in the nanoscale has produced, among numerous other things, materials used for and in drug delivery. Nanoparticles are generally considered to be solids whose diameter is varies between 1–1000 nm.
Although a number of solubilization technologies do exist, such as liposomes, cylcodextrins, microencapuslation, and dendrimers, each of these technologies has a number of significant disadvantages.
Phospholipids exposed to aqueous environment form a bi-layer structure called liposomes. Liposomes are microscopic spherical structures composed of phospholipids that were first discovered in the early 1960s (Bangham et al., J. Mol. Biol. 13: 238 (1965)). In aqueous media, phospholipid molecules, being amphiphilic, spontaneously organize themselves in self-closed bilayers as a result of hydrophilic and hydrophobic interactions. The resulting vesicles, referred to as liposomes, therefore encapsulate in the interior part of the aqueous medium in which they are suspended, a property that makes them potential carriers for biologically active hydrophilic molecules and drugs in vivo. Lipophilic agents may also be transported, embedded in the liposomal membrane. Liposomes resemble the bio-membranes and have been used for many years as a tool for solubilization of biological active molecules insoluble in water. They are non-toxic and biodegradable and can be used for specific target organs.
Liposome technology allows for the preparation of smaller to larger vesicles, using unilamillar (ULV) and multilamillar (MLV) vesicles. MLV are produced by mechanical agitation. Large ULV are prepared from MLV by extrusion under pressure through membranes of known pore size. The sizes are usually 200 nm or less in diameter, however, liposomes can be custom designed for almost any need by varying lipid content, surface change and method of preparation.
A number of companies such as Elan, Corp., Dublin, Ireland; Endorex Corp., Lake Forest, Ill.; Advanced Drug Deliveries Technologies, Muttenz, Switzerland; The Liposome Company, Inc., Princeton, N.J. (a subsidiary of Elan, Corp.); and Mibelle AG, Buchs, Switzerland, offer contract research and production facilities to the industry for the preparation of liposome inclusion complexes or inclusion moieties.
As drug carriers, liposomes have several potential advantages, including the ability to carry a significant amount of drug, relative ease of preparation, and low toxicity if natural lipids are used. However, common problems encountered with liposomes include: low stability, short shelf-life, poor tissue specificity, and toxicity with non-native lipids. Additionally, the uptake by phagocytic cells reduces circulation times. Furthermore, preparing liposome formulations that exhibit narrow size distribution has been formidable challenge under demanding conditions, as well as a costly one. Also, membrane clogging often results during the production of larger volumes required for pharmaceutical production of a particular drug.
Cyclodextrins are crystalline, water soluble, cyclic, non-reducing oligosaccharides built from six, seven, or eight glucopyranose units, referred to as alpha, beta and gamma cyclodextrin respectively, which have long been known as products that are capable of forming inclusion complexes. The cyclodextrin structure provides a molecule shaped like a segment of a hollow cone with an exterior hydrophilic surface and interior hydrophobic cavity.
The hydrophilic surface generates good water solubility for the cyclodextrin and the hydrophobic cavity provides a favorable environment in which to enclose, envelope or entrap the drug molecule. This association isolates the drug from the aqueous solvent and may increase the drug's water solubility and stability. For a long time most cyclodextrins had been no more than scientific curiosities due to their limited availability and high price.
As a result of intensive research and advances in enzyme technology, cyclodextrins and their chemically modified derivatives are now available commercially, generating a new technology: packing on the molecular level. Companies such as Cyclolab Ltd., Budapest, Hungary; Cydex, Inc., Overland Park, Kans.; and Cyclops, Inc., Reykjavik, Iceland, have been involved in the development and manufacture of cyclodextrins.
Cyclodextrins are, however, fraught with disadvantages. An ideal cyclodextrin would exhibit both oral and systemic safety. It would have water solubility greater than the parent cyclodextrins yet retain or surpass their complexation characteristics. The disadvantages of the cyclodextrins, however, include: limited space available for the active molecule to be entrapped inside the core, lack of pure stability of the complex, limited availability in the marketplace, and high price.
Microencapsulation is a process by which tiny parcels of a gas, liquid, or solid active ingredient (also referred to herein and used interchangeably with “core material”) are packaged within a second material for the purpose of shielding the active ingredient from the surrounding environment. These capsules, which range in size from one micron (one-thousandth of a millimeter) to approximately seven millimeters, release their contents at a later time by means appropriate to the application.
There are four typical mechanisms by which the core material is released from a microcapsule: (1) mechanical rupture of the capsule wall, (2) dissolution of the wall, (3) melting of the wall, and (4) diffusion through the wall. Less common release mechanisms include ablation (slow erosion of the shell) and biodegradation.
Microencapsulation covers several technologies, where a certain material is coated to obtain a micro-package of the active compound. The coating is performed to stabilize the material, for taste masking, preparing free flowing material of otherwise clogging agents etc. and many other purposes. This technology has been successfully applied in the feed-addition industry and to agriculture. The relatively high production cost needed for many of the formulations is, however, a significant disadvantage.
In the cases of nanoencapsulation and nanoparticles (which are advantageously shaped as spheres and hence, nanospheres), two types of systems having different inner structures are possible:                a) a matrix-type system composed of an entanglement of oligomer or polymer units, defined as nanoparticles or nanospheres and        b) a reservoir-type system, consisting of an oily core surrounded by a polymer wall, defined as a nanocapsule.        
Depending upon the nature of the materials used to prepare the nanospheres, the following classification exists:                a) amphiphilic macromolecules that undergo a cross-linking reaction during preparation of the nanospheres;        b) monomers that polymerize during preparation of the nanoparticles;        c) hydrophobic polymers, which are initially dissolved in organic solvents and then precipitated under controlled conditions to produce nanosparticles.        
Problems associated with the use of polymers in micro- and nanoencapsulation include: the use of toxic emulgators in emulsions or dispersions, polymerization or the application of high shear forces during emulsification process, insufficient biocompatibility and biodegrability, balance of hydrophilic and hydrophobic moieties, etc. These characteristics lead to insufficient drug release.
Dendrimers are a class of polymers distinguished by their highly branched, tree-like structures. They are synthesized in an iterative fashion from ABn monomers, with each iteration adding a layer or “generation” to the growing polymer. Dendrimers of up to ten generations have been synthesized with molecular weights in excess of 106 kDa. One important feature of dendrimeric polymers is their narrow molecular weight distributions. Indeed, depending on the synthetic strategy used, dendrimers with molecular weights in excess of 20 kDa can be made as single compounds.
Dendrimers, like liposomes, display the property of encapsulation; being able to sequester molecules within the interior spaces. Because they are single molecules, not assemblies, drug-dendrimer complexes are expected to be significantly more stable than liposomal drugs. Dendrimers are thus considered as one of the most promising vesicles for drug delivering systems. However, dendrimer technology is still in the research stage, and it is speculated that it will take years before the industry will apply this technology as a safe and efficient drug delivery system.
What is needed is a safe, biocompatible, stable and efficient drug delivery system that comprises nano-sized particles of an active ingredient for enhanced bioavailability and which overcomes the problems inherent in the prior art.